Organic compounds

ABSTRACT

The invention provides a novel process, novel process steps and novel intermediates useful in the synthesis of pharmaceutically active compounds, especially renin inhibitors, such as Allskiren. Inter alia, the invention provides a process for the manufacture of a compound of the formula III, 
     
       
         
         
             
             
         
       
     
     wherein R, R 1 , R 2 , R 3  and PG are as defined in the specification, or a salt thereof. The manufacture comprises (preferably consists of) reacting a compound of the formula I, 
     
       
         
         
             
             
         
       
     
     with a reagent able to transform hydroxy into X where X is for example a leaving group.

FIELD OF THE INVENTION

The invention relates to a novel process, novel process steps and novelintermediates useful in the synthesis of pharmaceutically activecompounds, especially renin inhibitors.

BACKGROUND OF THE INVENTION

Renin passes from the kidneys into the blood where it affects thecleavage of angiotensinogen, releasing the decapeptide angiotensin Iwhich is then cleaved in the lungs, the kidneys and other organs to formthe octapeptide angiotensin II. The octapeptide increases blood pressureboth directly by arterial vasoconstriction and indirectly by liberatingfrom the adrenal glands the sodium-ion-retaining hormone aldosterone,accompanied by an increase in extracellular fluid volume which increasecan be attributed to the action of angiotensin II. Inhibitors of theenzymatic activity of renin lead to a reduction in the formation ofangiotensin I, and consequently a smaller amount of angiotensin II isproduced. The reduced concentration of that active peptide hormone is adirect cause of the hypotensive effect of renin inhibitors.

With compounds such as (with INN name) allskiren((2S,4S,5S,7S)-5-amino-N-(2-carbamoyl-2-methylpropyl)-4-hydroxy-2-isopropyl-7-[4methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnonanamide),a new antihypertensive has been developed which interferes with therenin-angiotensin system at the beginning of angiotensin IIbiosynthesis.

As the compound comprises 4 chiral carbon atoms, the synthesis of theenantiomerically pure compound is quite demanding. Therefore, amendedroutes of synthesis that allow for more convenient synthesis of thissophisticated type of molecules are welcome.

It is therefore a problem to be solved by the present invention toprovide new synthesis routes and new intermediates allowing a convenientand efficient access to this class of compounds.

SUMMARY OF THE INVENTION

During investigation into the reductive de-oxygenation of adiastereomeric mixture of secondary benzylic alcohols of the formula Igiven below, an attempt was made to convert this group into a groupother than hydroxy, especially a leaving group such as halo, e.g. chloroor iodo, or a sultanate of organic sulfonic acids, e.g. methanesulfonate (mesylate) or toluolsulfonate (tosylate), in order tofacilitate the reductive process. However, the desired compounds werenot obtained. Instead of the desired compounds of the formula II

(which then, according to the original intentions, could have beenreduced to a corresponding compound wherein instead of X a hydrogen atomis present) wherein R, R₁, R₂, R₃ and PG are as defined for a compoundof the formula I below and X is a group other than hydroxy, especially aleaving group such as halo, e.g. chloro or iodo, or a sulfonate oforganic sulfonic acids, e.g. methane sulfonate (mesylate) ortoluolsulfonate (tosylate), pyrrolidines of the formula III given beloware obtained in high yield as single enantiomers, with thestereochemistry as indicated below. This surprising finding was thenutilised in a totally new route for the synthesis for allskiren andrelated compounds.

DETAILED DESCRIPTION OF THE INVENTION

In a first and very relevant aspect, the invention relates to a processfor the manufacture of a compound of the formula III,

wherein

R is hydrogen, alkyl or alkoxyalkyl;

R₁ is hydrogen, alkyl or alkoxyalkyl;

R₂ is hydrogen or preferably a hydroxyl protecting group;

R₃ is hydrogen or unsubstituted or substituted alkyl; and

PG is an amino protecting group, especially one removable by hydrolysis,e.g. lower alkoxycarbonyl, such as tert-butoxycarbonyl orbenzyloxycarbonyl; or a salt thereof;

said manufacture comprising (preferably consisting in)

reacting a compound of the formula I,

wherein R, R₁, R₂, R₃ and PG are as defined for a compound of theformula III, with a reagent able to transform (here especially benzylic)hydroxy (especially the one bound by a waved bond in formula I) into X(which is presumably at least temporarily present in a transitorycompound of the formula it as mentioned above in the reaction mixturebefore ring formation takes place) where X is a group other than hydroxyor hydrogen, especially a leaving group.

These compounds of formula (I) that are used as starting materials.These are accessible using a synthesis starting from (S) pyroglutamicacid. Reference is made to PCT application WO2006/024501 where ketoneamino derivatives of such compounds are prepared that can be convertedinto the respective amino alcohol by hydrogenation or reduction.

A reagent able to transform hydroxy into X preferably is a customaryreagent for the conversion of a benzylic alcohol into a group other thanhydroxy, especially leaving group X, e.g. where X is halo selected fromthe group consisting of (e.g. aqueous) hydrohalic acids, such ashydrochloric acid, a thionyl halogenide, such as thionyl chloride, PX*₃,PDX*₃, PX*₅ or PDX*_(S) wherein X* is halogen (so that the X resultingin a, especially chloro or bromo, a combination oftriphenylphosphine/halogen, such as triphenylphosphine/iodine, where Xis an organic sulfonyloxy moiety an active derivative (formable undercomparable conditions as shown below for activation of an activederivative of a carbonic acid of the formula XVI, also in situ,especially an anhydride (e.g. the mixed anhydride with a carbonic acid,such as acetic acid, or a symmetric anhydride) or halogenide of anorganic sulfonic acid, such as methanesulfonyl chloride,trifluoromethanesulfonylchloride or tosylchloride, in the presence of abase, e.g. a tertiary nitrogen base, such as triethylamine, or the like.In the case of a thionyl halogenide, PX*₃, PDX*₃, PX*s or POX*s, thereaction preferably takes place in an appropriate solvent, such astoluene, in the presence of a tertiary nitrogen base, such as pyridine,e.g. at reaction temperatures from 0 to 50° C. In the presence of ananhydride or halide of an organic sulfonic acid, the reaction preferablytakes place in the presence of an appropriate solvent, such as tolueneand/ or dimethylaminopyridine, and a base, e.g. a tertiary nitrogenbase, such as triethylamine, e.g. at temperatures from −30 to 50° C. Inthe presence of triphenylphosphine/halogen, the reaction preferablytakes place in an appropriate solvent, such as toluene and/oracetonitrile, in the presence of a (preferably cyclic unsaturated)nitrogen base, such as imidazole, at temperatures e.g. from 0 to 50° C.

Alternatively, compound (Hi) can be obtained from compound (I) using anion exchange resin, preferably an acidic ion exchange resin such anamberlyst acidic ion exchange resin, preferably Amberlyst 15 (Fluke)under the elimination of water. The reaction preferably takes place inthe presence of an appropriate solvent, such as toluene and/oracetonitrile, at temperatures e.g. from 0 to 50° C. such as roomtemperature.

Another important embodiment of the invention relates to a compound ofthe formula III as defined above, or a salt thereof.

A compound of the formula III may be used, inter alfa, for the synthesisof pharmaceutically active substances, preferably renin inhibitors suchas allskiren, especially as described in the following.

In a preferred further embodiment of the invention, this synthesiscomprises as a further step or as individual synthesis the (partial)deprotection of a compound of the formula III (which in free form or assalt is also as such a preferred embodiment of the invention) wherein R₂is a hydroxy protecting group, especially one removable by deprotectionconditions other than those required for removal of PG, more preferablyby hydrolysis, e.g. tert-C₄-C₇-alkoxacarbonyl, such astert-butoxycarbonyl, while R, R₁, R₃ and PG are as defined for acompound of the formula I above, under removal of the protecting groupR₂ to a compound of the formula IV.

wherein R, R₁, R₃ and PG are as defined under formula III above, or asalt thereof. A compound of the formula IV, or a salt thereof, is alsoas such a preferred embodiment of the invention.

In the case of a protecting group R₂ removable by hydrolysis, e.g.tert-C₄-C₇-alkoxycarbonyl such as tert-butoxycarbonyl, the removalpreferably takes place in the presence of an acid or more preferably abase, such as a metal hydroxide or preferably a metal, more preferablyan alkali metal carbonate, such as potassium carbonate, in anappropriate solvent, such as an alcohol, e.g. methanol or ethanol, wateror a mixture thereof. e.g. at temperatures from 0° C. to the refluxtemperature of the mixture, for example from 30 to 60° C.

As an alternative to reaction steps described above, compound (I)—alsocrude (I)—can be transformed in a one-pot synthesis to compound (IV) asthe free base (IVa), which may be purified by extraction, withoutisolation of the intermediate compound of formula (III), compound (IVa)then can be crystallized as a salt such as the maleate or oxalate. Thisis preferred as it allows further purification. Compound (IVa) is easilytransformed to compound (IV). The introduction of the protecting groupat the nitrogen is simple, selective and clean.

In this sequence, a protecting group R₂ and PG are preferably removableby hydrolysis and are more preferably, e.g. tert-C₄-C₇alkoxycarbonylsuch as tert-butoxycarbonyl. The removal preferably takes place in thepresence of an base or more preferably an acid under conditions wellknown in the art, such as using an inorganic acid preferably as anaqueous or alcoholic solution thereof such as HCl, trtfluoroacetic acid,sulfuric acid, phosphoric acid, methane sulfonic acid, etc. in anappropriate solvent, such as an alcohol, e.g. methanol or ethanol,esters like ethylacetate or isopropyl acetate, or ethers like THF orTBME, water or a mixture thereof, e.g. at temperatures from 0° C. to thereflux temperature of the mixture, for example from 50 to 100° C.

If a crystallization of compound (IVa) is desired, this is performed bytypical crystallization techniques and adding the desired acid such asmaleic acid or oxalic acid, preferably maleic acid.

Protection of the pyrrolidine amino group is effected by methods knownin the art such as those described hereinafter in the examples or asreferred to in the cited textbooks. Preferably, a boc group isintroduced at the nitrogen using e.g. di-tert-butyl dicarbonate understandard conditions.

A compound of the formula IV can then be further used in a number ofways in the synthesis of renin inhibitors such as allskiren.

In a first further embodiment of the invention; a process for thesynthesis of a renin inhibitor, such as allskiren, comprises oxidizing acompound of the formula IV, especially synthesized as in the precedingsteps, to an oxo compound of the formula V,

wherein R, R₁, R₃ and PG are as defined under formula III above, or asalt thereof. This process step as such, as well as a compound of theformula V, or a salt thereof, also form embodiments of the invention.

The reaction especially takes place under customary conditions thatallow for the oxidation of a hydroxy group to an oxo group and employingcustomary oxidizing reagents (oxidants).

In the (preferred) case where R₃ in a compound of a formula IV ishydrogen, this reaction can make use of such oxidants that allow for thedirect obtaining from a compound of the formula IV of a correspondingaldehyde of the formula V, or a salt thereof, or it can be lead by firstoxidizing to a carboxyl compound of the formula XVI,

wherein R, R₁ and PG are as defined above for a compound of the formulaIII, or a salt thereof, which can then be reduced with reducing agentsto an aldehyde of the formula V wherein R₃ is hydrogen and wherein R,R₁, R₃ and PG are as defined under formula III above, or a salt thereof.These process steps as such, as well as a compound of the formula XVI,or a salt thereof, and a compound of the formula V, or a salt thereof,also form embodiments of the invention. The direct reaction to analdehyde of the formula V, can, for example, take place in the presenceof an oxidant that allows for the oxidation of an alcohol to an aldehydewithout undue formation of the acid of the formula XVI, e.g. underOppenauer conditions (e.g. using cyclohexanone, cinnamic aldehyde oranisaldehyde as oxidant in the presence of an aluminium alcoholate, suchas aluminium-tert.-butoxyalcoholate), preferably with chromic acid,dichromate/sulphuric acid, pyridinium-chlorochromate, pyridiniumdichromate, nitric acid, manganese dioxide or selenium dioxide or bycatalytic dehydrogenation, or more preferably using oxidants usefulunder mild reaction conditions, such as TEMPO oxidation(TEMPO=2,2,6,6-tetramethylpiperidine-nitroxyl) with bleach, e.g. sodiumsodium chlorite or calcium hypochlorite, preferably in the presence of abromide salt, e.g. potassium bromide, in an appropriate solvent, such asmethylene chloride and for water, or with diacetoxyiodobenzene in anappropriate solvent, e.g. methylene chloride, at temperatures e.g. from0 to 50° C.; under Swam conditions, e.g. using dimethylsulfoxide in thepresence of oxalyl chloride, e.g. at lowered temperatures, such as from−90 to 0° C., preferably in the presence of a tertiary nitrogen base,such as triethylamine or diisopropylethylamine; under Corey-Kimconditions, e.g. using dimethylsulfide in the presence ofN-chloro-succinimide; using Moffat-Plitzner conditions, e.g. oxidationwith dimethylsulfoxide in the presence of dicyclohexylcarbodiimide;Dess-Martin oxidation in the presence of Dess-Martin-periodinane(1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one) in anappropriate solvent, such as methylene chloride, e.g. at temperaturesfrom 0 to 50° C.; or using SO₃/pyridine complex in dimethylsulfoxide inthe absence or presence of an appropriate solvent such as methylenechloride at temperatures e.g. from −30 to 30° C.; or with lowerpreference using catalytic dehydrogenation, e.g. in the presence ofsilver, copper, copper chromium oxide or zinc oxide. Where required, thestoichiometry of the oxidants is chosen appropriately to avoidover-oxidation.

The oxidation of a compound of the formula IV (or alsban aldehydecompound of the formula V obtained preferably as described above) to acompound of the formula XVI can, for example, take place with Jonesreagent (CrO₃ in aqueous sulphuric acid/acetone), with manganesedioxide, with pyridinium dichromate or especially under Pinnickoxidation conditions, e.g. by oxidation with sodium chlorite or calciumhypochlorite in the presence of a weak acid, preferably an alkali metaldihydrogenphosphate, e.g. sodium dihydrogenphosphate. in an appropriatesolvent or solvent mixture. e.g. an alcohol, such as tert-butanol,2-methyl-2-butene and/or water, at temperatures e.g. from 0 to 50° C.The reduction of an acid compound of the formula XVI then can take placeusing reducing agents that allow for the selective reduction to analdehyde of the formula V wherein R₃ is hydrogen and wherein R, R₁, R₃and PG are as defined under formula III. The reducing agents can, forexample, be selected from appropriate complex hydrides, such as, and thecompound of the formula XVI can also be used in a form with activatedcarboxyl group, e.g. as acid halogenide, active ester, (e.g. mixed)anhydride or by in situ activation, e.g. in an active form or byactivation as described below for the coupling of a compound of theformula XVI and a compound of the formula VI. For example, in the caseof an acid chloride of a compound of the formula XVI, the reduction toan aldehyde of the formula V can take place with LiAlH(tert-butoxy)₃(lithium-tri(tert-butoxy)aluminiumhydride) in an appropriate solvent,e.g. 2-methoxyethyl ether (diglyme), or sodium borohydride or complexesthereof can be used. Alternatively, the reduction can take place byhydrogenation in the presence of partially poisoned hydrogenationcatalysts, e.g. under Rosenmund reduction conditions usingpalladium/barium sulfate and hydrogen in an appropriate solvent, such aswater, an alcohol, such as methanol or ethanol, dioxane, acetyl acetateor mixture of tow or more such solvents, at customary temperatures, e.g.from 0 to 80° C.

In a further embodiment of said first embodiment of the invention, aprocess for the synthesis of a renin inhibitor, such as allskiren,comprises reacting a compound of the formula V as just defined with theproviso that R₃ in it is hydrogen under Grignard or Grignard-likeconditions with a reagent prepared by reaction of a compound of theformula VI,

wherein Hal is halo, preferably chloro, bromo or iodo, and PT is ahydroxyl protecting group, with a metal, to give a compound of theformula VII.

wherein R, R₁ and PG are as defined under formula III and PT is ahydroxyl protecting group, preferably one that can be selectivelyremoved without removal of the protecting group PG, e.g.1-phenyl-C₁-C₇-alkyl, such as benzyl, or a salt thereof. This processstep as such, as well as a compound of the formula VII, or a saltthereof, also form embodiments of the invention. Thediastereoselectivity of this reaction can be very high, e.g. larger than99:1, that is, the other possible diastereoisomer is practically notobserved. This shows a high advantage of the use of the pyrrolidine ringsystem for this conversion and thus also in the synthesis of renininhibitors such as allskiren.

The reaction preferably takes place with a metal reacting with thecompound of the formula VI to give the corresponding metal compound,e.g. a lithium, sodium, iron, zinc, tin, indium, manganese, aluminium orcopper metal compound, or MaX, (alkyl)₃MnLi−, or —CeX₂ wherein X ishalogen such as Cl, I or Br, more preferably Br, or further a reagentobtainable with metal combinations, such as Mg/Fe, or still further withLewis adds, such as BF₃ diethyl ether complex or MgBr₂, or the like, togive a Grignard-like reagent for Grignard-like reaction, or withmagnesium giving the corresponding Grignard reagent with magnesium (Mg)as the metal for Grignard reaction, in an appropriate solvent, e.g. anether, such as a cyclic ether, e.g. tetrahydrofuran, an alkyl ether,e.g. diethyl ether, tert-butylmethyl ether, a hydrocarbon, such astoluene, or a halogenated hydrocarbon, e.g. methylene chloride, attemperatures e.g. in the range from 0 to 70° C. Grignard orGrignard-like reagents or organo lithium compounds are preferred, andGrignard or Grignard-like reagents are particularly preferred.

Compound of formula (Vi) can be prepared according to methods well knownto the person skilled in the art, see e.g., Houben-Weyl, Vol. 13/2a,page 53-526, which is incorporated herein by reference.

In a further embodiment of said first embodiment of the invention, aprocess for the synthesis of a renin inhibitor, such as allskiren,comprises deprotecting a compound of the formula VII as just defined byremoval of the hydroxy protecting group PT, for example in the case of aprotecting group that can be removed by hydrogenation such as1-phenyl-C₁-C₇-alkyl, e.g. benzyl, by catalytic hydrogenation, to give acompound of the formula VIII,

wherein R, R₁ and PG are as defined under formula III above, or a saltthereof. This process step as such, as well as a compound of the formulaVIII, or a salt thereof, also form embodiments of the Invention. Thedeprotection takes place under standard conditions, e.g. in the case ofremoval of the protecting group by hydrogenation with hydrogen in thepresence of a catalyst, such as a noble metal catalyst. e.g. palladium,which may be present on a carrier, such as charcoal, in an appropriatesolvent, such as an alcohol, e.g. methanol or ethanol, or non-alcoholicsolvents such as (but not restricted to) toluene or ethyl acetate, atappropriate temperatures, e.g. in the range from 0 to 50° C.

In a further embodiment of said first embodiment of the invention, aprocess for the synthesis of a renin inhibitor, such as allskiren,comprises oxidizing a compound of the formula VIII at the primaryhydroxy group to an aldehyde compound of the formula IX,

wherein R, R₁ and PG are as defined under formula III above, or a saltthereof, which then cyclizes spontaneously to produce a factol of theformula X,

which, either in the same reaction mixture (in situ) or after isolationand in a separate process step, which as such also forms an embodimentof the invention, is then oxidized to a lactone of the formula XI,

wherein in formula X and XI R, R₁ and PG are as defined for a compoundof the formula III above. This sequence of reaction steps from reactionof a compound of the formula VIII to a compound of the formula XI assuch, as well as a compound of the formula IX or especially a compoundof the formula X and/or XI, or salts thereof, also farm embodiments ofthe invention. The oxidation of a compound of the formula VIII resultingin the lactol of the formula X preferably takes place under theconditions mentioned to be preferred for oxidation of a compound of theformula IV to an aldehyde of the formula V, e.g. with SO₃/pyridine inthe presence of dimethylsulphoxide in an appropriate solvent, such asmethylene chloride, preferably in the presence of a tertiary nitrogenbase, such as triethylamine, e.g. at temperatures from −30 to 50° C. Thesubsequent oxidation to the compound of the formula XI can take placeunder the same reaction conditions employing an excess of some of thereagents mentioned above or it can be isolated and oxidized separatelywith further reagents, e.g. those mentioned above, more preferably usingTEMPO/diacetoxyiodo benzene.

Alternatively, it can also be oxidized at the primary alcohol withouteffecting the secondary alcohol to compound XI with the reagent TPAP(Tetra-N-propylammonium perruthenate) e.g. according to lit. ref., S.Ley et al. Synthesis, 639 (1994). This method is particularly preferred.

In a further embodiment of said first embodiment of the invention, aprocess for the synthesis of a renin inhibitor, such as allskiren,comprises reacting a compound of the formula XI as just defined, or asalt thereof, with an amine of the formula XII,

(wherein the amido nitrogen can also be protected if desired and theprotecting group then be removed in the corresponding protected compoundof the formula XIII), or a salt thereof, obtaining a compound of theformula XIII,

wherein R, R₁ and PG are as defined for a compound of the formula III,or a salt thereof. This process step as such, as well as a compound ofthe formula XIII, or a salt thereof, also form embodiments of theinvention.

The reaction preferably takes place under standard conditions for theformation of an amide from a lactone, e.g. in an appropriate solvent orsolvent mixture, e.g. in an ether, such as tert-butylmethyl ether,preferably in the presence of a bifunctional catalyst with a weak acidicand a weak basic group, e.g. 2-hydroxypyridine or proline, in thepresence of an appropriate base, e.g. a tertiary nitrogen base, such astriethylamine, at appropriate temperatures e.g. In the range from 0° C.to the reflux temperature of the reaction mixture, e.g. from 0 to 85° C.

In a further embodiment of said first embodiment of the invention, aprocess for the synthesis of a renin inhibitor, such as allskiren,comprises opening the ring in a compound of the formula XIII byreductive or hydrogenolytic ring opening to a compound of the formulaXIV,

wherein R, R₁ and PG are as defined for a compound of the formula III,or a salt thereof. This reaction step as such also forms an embodimentof the invention.

The reductive ring opening preferably takes place under conditionsemploying appropriate metals as reductants, e.g. under conditionscomparable to those of a Birth reduction with alkali metals and liquidammonia, e.g. with sodium or lithium in the presence of liquid ammonia(NH₃) in the presence or absence of an appropriate further solvent orsolvent mixture, such as an ether, e.g. tetrahydrofurane, and/or analcohol, e.g. ethanol, at lower temperatures, e.g. from −90 to −20° C.,e.g. at about −78° C. Alternative reductions methods are possible, e.g.reduction with calcium in tert-butanol, other reduction methods withcalcium, lithium-di-tert-butylbiphenytide, magnesium in anthracene, orthe like, which do not require the use of liquid ammonia and lowtemperatures (<−20° C.).

Alternatively, the ring opening may be effected by hydrogenation. Suchmethods are well known in the art and are described e.g. in Houben-Weyl,Volume 11/1, Stickstoffverbindungen II, page 968-971 or D. Touivre, etal_, Tetrahedron, 54, 1753 (1998).

In a further embodiment of said first embodiment of the invention, aprocess for the synthesis of a renin inhibitor, such as allskiren,comprises deprotecting a compound of the formula XIV to give thecorresponding compound of the formula XV,

which is pharmaceutically active, especially as a renin inhibitor,wherein R and R₁ are as defined for a compound of the formula I, or asalt thereof; and, if desired, converting an obtainable free compound ofthe formula XV into a salt or an obtainable salt into the free compoundof the formula XV or a different sail thereof. For example, if PG is(what is preferred) a C₁-C₇-alkoxycarbonyl group, such astert-butoxycarbonyl, the removal can take place under customaryconditions, e.g. In the presence of an acid, such as hydrohalic acid, inan appropriate solvent, such as dioxane, e.g. at temperatures from 0 to50° C., for example at room temperature.

An especially important aspect of the invention relates to a process forthe manufacture of a compound of the formula XV, or a salt thereof,comprising first opening the ring in a compound of the formula XIII asdescribed above by reducing it selectively to a compound of the formulaXIV as described above, or a salt thereof, and then deprotecting acompound of the formula XIV to give the corresponding compound of theformula XV, or a salt thereof, and, if desired, converting an obtainablefree compound of the formula XV into a salt or an obtainable salt intothe free compound of the formula XV or a different salt thereof.

In a second further embodiment according to the invention, a process forthe synthesis of a renin inhibitor, such as allskiren, comprisesreacting a compound of the formula XVI (which can be obtained asdescribed above or by first oxidizing a compound of the formula IVwherein R₃ is hydrogen, this reaction can make use of such oxidants thatlead to a corresponding aldehyde of the formula V, or a salt thereof,and than oxidizing the aldehyde of the formula V further to the carbonicacid of the formula XVI, or a salt thereof, e.g. by reactions analogousto those described above) as described above, or a salt thereof(obtainable preferably as described above where the synthesis of acompound of the formula XVI is first described) wherein R, R₁ and PG areas defined above for a compound of the formula III, or a salt thereof,with a reagent capable of activating the carboxyl group, especiallycapable of transforming it into an acid halide, a mixed acid anhydride acarbonyl imidazolide or a “Weinreb amide”, and then reacting it with ametallo-organic derivative of a compound of the formula VI as definedabove, especially a zinc, lithium or magnesium derivative, to a compoundof the formula XVII,

wherein R, R₁ and PG are as defined for a compound of the formula IIIand PT is as defined for a compound of the formula VI, or a saltthereof. This process step as such, as well as a compound of the formulaXVII, or a salt thereof, also form embodiments of the invention.

The activating of the carboxyl group in a compound of the formula XVI toform a reactive derivative thereof preferably takes place undercustomary condensation conditions, where among the possible reactivederivatives of an acid of the formula XVI reactive esters (such as thehydroxybenzotriazole (HOBT), pentafluorophenyl, 4-nitrophenyl orN-hydroxysuccinimide ester), imidazolide, a “Weinreb amide”, acidhalogenides (such as the acid chloride or bromide) or reactiveanhydrides (such as mixed anhydrides with lower alkanoic acids orsymmetric anhydrides) are preferred. Reactive carbonic acid derivativescan also be formed in situ. The reaction is carded out by dissolving thecompounds of formula XVI in a suitable solvent, for example ahalogenated hydrocarbon, such as methylene chloride,N,N-dimethylformamide. N,N-dimethylacetamide, N-methyl-2-pyrrolidone,methylene chloride, or a mixture of two or more such solvents, and bythe addition of a suitable base, for example triethytamine,diisopropylethylamine (DEA) or N-methylmorpholine and, it the reactivederivative of the acid of the formula II is formed in situ, a suitablecoupling agent that forms a preferred reactive derivative of thecarbonic acid of formula XVI in situ, for exampledicyclohexylcarbodiimide/1-hydroxybenzotriazole (DCC/HOBT);bis(2-oxo-3-oxazolidinyl)phosphonic chloride (BOPCI);O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TPTU); O-benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU);(benzotriazol-1-yloxy)-tripyrrolidinophosphonium-hexafluorophosphate(PyBOP), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride/hydroxybenzotriazole or/1-hydroxy-7-azabenzotriazole(EDC/HOBT or EDC/HOAt) or HOAt alone, or with(1-chloro-2-methyl-propenyl)-dimethylamine. The reaction mixture ispreferably stirred at a temperature of between approximately −20 and 50°C., especially between 0° C. and 30° C., e.g. at room temperature. Thereaction is preferably carried out under an inert gas, e.g. nitrogen orargon.

The subsequent reaction with a metallo-organic derivative of a compoundof the formula VI, especially a zinc, lithium or magnesium derivative,or further a manganese, aluminium or copper derivative, then preferablytakes place under customary conditions, e.g. analogous to the Grignardor Grignard-like conditions mentioned above for the reaction of acompound of the formula VI with an aldehyde of the formula V.

In a further embodiment of said second embodiment of the invention, aprocess for the synthesis of a renin inhibitor, such as allskiren,comprises reducing a compound of the formula XVII under stereoselectiveconditions and deprotecting the resulting compound under removal of thehydroxy protecting group PT to give a compound of the formula VIII asdescribed above, or a salt thereof.

The reduction under stereoselective conditions preferably takes place inthe presence of a stereoselective reductant, such asLiAlH(O-tert-butyl)₃, LiBH(sec-butyl)₃ (Selectride®), potassiumselectride, or borohydride/oxaazaborolidine ((“CBS-catalysts” originallybased on the work of Corey, Bakshi and Shibata, synthesizable in situfrom an amino alcohol and borane), or by stereoselective hydrogenation,e.g. in the presence of catalysts such as [Ru₂Cl₄((S- or R-)BINAP)]NEt₃;the reactions take place under customary conditions, e.g. in appropriatesolvents, such as tetrahydrofuran, methanol, ethanol, or mixtures of twoor more such solvents, e.g. at temperatures from −80 to 50° C. (see, forexample, Rüeger et al., Tetrahedron Letters, 2000, 41, 10085.)

The deprotection then takes place under standard conditions, e.g. if PTis a protecting group that can be removed by hydrogenation such as1-phenyl-C₁-C₇-alkyl, e.g. benzyl, by catalytic hydrogenation, forexample under conditions analogous to those mentioned above fordeprotection of a compound of the formula VII.

A compound of the formula VIII can be further reacted to a compound ofthe formula X, or a salt thereof, as described above, which then can befurther reacted via the reaction steps shown above to yield a compoundof the formula XV, or a salt thereof.

Alternatively, a compound of the formula VIII as defined above, or asalt thereof, obtainable or preferably obtained either according to thefirst or the second embodiment of the invention, can be further reactedto a compound of the formula XVIII,

wherein R, R₁ and PG are as defined for a compound of the formula III,or a salt thereof, by reductive or hydrogenolytic ring opening of thepyrrolidine ring. This process step as such, as well as a compound ofthe formula XVIII, or a salt thereof, also form an embodiment of theinvention. The reductive or hydrogenolytic ring opening preferably takesplace under conditions as those mentioned above for the ring opening ina compound of the formula XIV.

Alternatively, a compound of the formula VII as defined above, or a saltthereof, obtainable or preferably obtained either according to the firstor the second embodiment of the invention, can be further reacted to acompound of the formula XVIII directly without a separate deprotectionstep,

wherein R, R₁ and PG are as defined for a compound of the formula ill,or a salt thereof, by reductive or hydrogenolytic ring opening of thepyrrolidine ring. This process step as such, as well as a compound ofthe formula XVIII, or a salt thereof, also form an embodiment of theinvention. The reductive or hydrogenolytic ring opening preferably takesplace under conditions as those mentioned above for the ring opening ina compound of the formula XIV. This method is particularly preferredwhen PT is a protecting group removable under the conditions of thereductive opening, in particular, if PT is phenyl-C₁-C₇-alkyl, such asbenzyl.

A compound of the formula XVIII can then be oxidized in a furtherembodiment of said first or second embodiment of the invention in aprocess for the synthesis of a renin inhibitor, such as allskiren,(comparably as a compound of the formula VIII via an aldehyde withopened pyrrolidine ring analogous to a compound of the formula IX,preferably under conditions as described for that reaction) to a lactolof the formula XIX,

wherein R, R₁ and PG are as defined for a compound of the formula III,or a salt thereof (where both this reaction as well as a compound of theformula XIX, or a salt thereof, as such are also embodiments of thepresent invention), which, either in the same reaction mixture (in situ)or after isolation, is then oxidized to a lactone of the formula XX

wherein R, R₁ and PG are as defined for a compound of the formula III,or a salt thereof (where this reaction as such is also an embodiment ofthe present invention), the reaction preferably taking place underconditions analogous to those described above for oxidation a compoundof the formula X to a compound of the formula Xt. A lactone of theformula XX, or a salt thereof, can also be obtained directly from acompound of the formula XVIII. In this case, the reaction alsopreferably taking place under conditions analogous to those describedabove for oxidation a compound of the formula X to a compound of theformula XI A lactone of the formula XX, or a salt thereof, is also apreferred new embodiment according to the invention.

A compound of the formula XX can then, in a further embodiment of saidfirst or second embodiment of the invention in a process for thesynthesis of a renin inhibitor, such as allskiren, be reacted with acompound of the formula XII defined above (if in protected form withsubsequent deprotection of the amide nitrogen), preferably underanalogous reaction conditions as described there, to a compound of theformula XIV as described above, or a salt thereof (where this reactionas such also is an embodiment of the invention. The latter can then bedeprotected as described above to give the final product of the formulaXV described above, or a salt thereof.

In a third embodiment of the invention, a process for the synthesis of arenin inhibitor, such as allskiren, comprises reacting a compound of theformula VII, or a salt thereof, as defined above (obtainable accordingto the first or second embodiment of the invention) by reductive orhydrogenolytic ring opening to a compound of the formula)(Xi,

wherein R, R₁ and PG are as defined for a compound of the formula IIIand PT is a hydroxy protecting group, or a salt thereof, (where thisreaction step as such, as well as a compound of the formula XXI, or asalt thereof, especially wherein PG=benzyloxycarbonyl and PT is benzylor wherein PG is hydrogen and PT is benzyl, also form embodiments of theinvention. The reductive or hydrogenolytic ring opening preferably takesplace under conditions as those mentioned above for the ring opening ina compound of the formula XIV. A compound of the formula XXI, or a saltthereof, can then be reacted in analogy to a compound of the formulaVIII above by removal of the protecting group to give a compound of theformula XVIII as described above, or a salt thereof, which can then befurther transformed e.g. via compounds XIX and XX and XIV and preferablyunder analogous reaction conditions, or in each case a salt thereof, toa compound of the formula XV as defined above, or a salt thereof.

In a fourth embodiment of the invention, a process for the synthesis ofa renin inhibitor, such as allskiren, comprises reacting a compound ofthe formula X, or a salt thereof, as defined above, by reductive orhydrogenolytic ring opening to a compound of the formula XIX as shownabove, or a salt thereof, which reaction as such is also an embodimentof the invention. The reductive or hydrogenolytic ring openingpreferably takes place under conditions as those mentioned above for thering opening in a compound of the formula XIV.

In a further embodiment of said fourth embodiment of the invention, aprocess for the synthesis of a renin inhibitor, such as allskiren,comprises oxidising a compound of the formula XIX, or a salt thereof, togive a lactone compound of the formula XX, or a salt thereof, asdescribed above (preferably under reaction conditions analogous to thosefor oxidation of a compound of the formula X to a compound of theformula XI as given above) which, in yet a further embodiment of saidfourth embodiment of the invention, can then be reacted with a compoundof the formula XII, or a salt thereof, as described above, preferablyunder reaction conditions analogous to those described for reaction of acompound of the formula XI with a compound of the formula XII, to give acompound of the formula XIV as described above, or a salt thereof, whichcan then, in a further embodiment of said fourth embodiment of theinvention, be deprotected into a compound of the formula XV, or a saltthereof, as described above, preferably under analogous conditions asdescribed above for the deprotection of a compound of the formula XIV.

In a fifth embodiment of the invention, a process for the synthesis of arenin inhibitor, such as allskiren, comprises reacting a compound of theformula XI as described above, or a salt thereof, by reductive orhydrogenolytic ring opening to give a compound of the formula XX, or asalt thereof, as described above (where this reaction as such also formsan embodiment of the invention). The reductive or hydrogenolytic ringopening preferably takes place under conditions as those mentioned abovefor the ring opening in a compound of the formula XIV.

In a further embodiment of said fifth embodiment of the invention, aprocess for the synthesis of a renin inhibitor, such as allskiren,comprises reacting a compound of the formula XX, or a salt thereof, witha compound of the formula XII, or a salt thereof, as described above,preferably under reaction conditions analogous to those mentioned abovefor reaction of a compound of the formula XI with a compound of theformula XII, to give a compound of the formula XIV as described above,or a salt thereof, which can then, in a further embodiment of said fifthembodiment of the invention, be deprotected into a compound of theformula XV, or a salt thereof, as described above,*preferably underreaction conditions analogous to those described above for deprotectionof a compound of the formula XIV.

In a sixth embodiment of the invention, a process for the synthesis of arenin inhibitor, such as allskiren, comprises reacting a compound of theformula V as described above, or a salt thereof, wherein R₃ is hydrogen,with a compound of the formula XXII,

wherein Y is Ph₃P* or (AlkO)₂P(O) wherein Alk is preferably alkyl, e.g.C₁-C₇-alkyl, (both of which may also be prepared in situ, respectively)and Rx is hydroxy, protected hydroxy, amino or NH—CH₂C(CH₃)₂—CONH₂,resulting in a compound of the formula XXIII,

wherein R, R₁ and PG are as defined for a compound of the formula IIIand Rx is as defined for a compound of the formula XXII; or a saltthereof. This process step as such, as well as a compound of the formulaXXIII, or a salt thereof, also form embodiments of the invention. Herethe reaction can take place in the presence of a suitable base, forexample, sodium hydride, butyllithium, hexyllithium, cyclohexyllithiumor lithium diisopropylamide, in appropriate solvents, such as ethers,e.g. tetrahydrofuran, hydrocarbons, e.g. toluene, or halogenatedhydrocarbons, e.g. methylene chloride or mixtures of two or more suchsolvents, for example at temperatures between −78° C. and 100° C.

In a further embodiment of said sixth embodiment of the invention, aprocess for the synthesis of a renin inhibitor, such as allskiren,comprises reacting a compound of the formula XXIII, or a salt thereof,under reductive or hydrogenolytic opening of the pyrrolidine ring andformation of an aziridine ring in formula XXIII to give a compound ofthe formula XXIV,

wherein R, R₁ and PG are as defined for a compound of the formula IIIand Rx is as defined for a compound of the formula XXII, or a saltthereof. This process step as such, as well as a compound of the formulaXXIV, or a salt thereof, also form embodiments of the invention. Thereductive or hydrogenolytic ring opening preferably takes place underconditions as those mentioned above for the ring opening in a compoundof the formula XIV.

In a further embodiment of said sixth embodiment of the Invention, aprocess for the synthesis of a renin inhibitor, such as allskiren,comprises reacting a compound of the formula) XXIV, or a salt thereof,under ring opening to give a compound of the formula XX, or a saltthereof, if Rx in the compound of the formula is OH (or if it isprotected hydroxy and the hydroxy protecting group is first removed togive OH). The ring opening reaction can, for example, take place underacidic or basic conditions, preferably in the presence of appropriatesolvents, for example alcohols, such as ethanol or methanol, ethers,such as tetrahydrofuran, hydrocarbons, such as toluene, or halogenatedhydrocarbons, such as methylene chloride, for example at temperaturesbetween 0° C. and the reflux temperature of the respective reactionmixture. A compound of the formula XX, or a salt thereof, can then, in afurther preferred embodiment of the sixth embodiment of the invention,be converted into a compound of the formula XIV as described above, or asalt thereof, by reacting it with a compound of the formula XII asdefined above to a compound of the formula XIV as defined above,preferably under reaction conditions analogous to those mentioned above;which, in a further preferred embodiment of the sixth embodiment of theinvention, can then be deprotected to a compound of the formula XV, or asalt thereof, preferably under conditions analogous to those describedabove for deprotection of a compound of the formula XIV.

In yet a further embodiment of said sixth embodiment of the invention, aprocess for the synthesis of a renin inhibitor, such as allskiren,comprises reacting a compound of the formula XXIV, or a salt thereof,wherein Rx is NH—CH₂C(CH₃)₂—CONH₂, under ring opening (with conditionspreferably analogous to those described in the preceding paragraph) togive a compound of the formula XIV, or a salt thereof. The latter canthen, in a further preferred embodiment of this version of the sixthembodiment of the invention, be deprotected to a compound of the formulaXV, or a salt thereof, preferably under conditions analogous to thosedescribed above for deprotection of a compound of the formula XIV.

All these different synthesis routes show that with the compound of theformula III a highly important new compound has been found that is acentral Intermediate to a number of possible synthesis routes especiallyfor the synthesis of renin inhibitors such as allskiren. Therefore, thiscompound of the formula III, or a salt thereof, as well as its synthesisform very highly preferred embodiments of the invention.

Listed below are definitions of various terms used to describe the novelintermediates and synthesis steps of the present invention. Thesedefinitions, either by replacing one, more than one or all generalexpressions or symbols used in the present disclosure and thus yieldingpreferred embodiments of the invention, preferably apply to the terms asthey are used throughout the specification unless they are otherwiselimited in specific instances either individually or as part of a largergroup.

The term “lower” or “C₁-C₇-” defines a moiety with up to and includingmaximally 7. especially up to and including normally 4, carbon atoms,said moiety being branched (one or more times) or straight-chained andbound via a terminal or a non-terminal carbon. Lower or C₁-C₇-alkyl, forexample, is n-pentyl, n-hexyl or n-heptyl or preferably C₁-C₄-alkyl,especially as methyl, ethyl, n-propyl, sec-propyl, n-butyl, isobutyl,sec-butyl, tert-butyl.

Halo or halogen is preferably fluoro, chloro, bromo or iodo, mostpreferably fluoro, chloro or bromo; where halo is mentioned, this canmean that one or more (e.g., up to three) halogen atoms are present,e.g. in halo-C₁-C₇-alkyl, such as trifluoromethyl. 2,2-difluoroethyl or2,2,2-trifluoroethyl,

Alkyl preferably has up to 20 carbon atom and is more preferablyC₁-C₇alkyl. Alkyl is straight-chained or branched (one or, if desiredand possible, more times). Very preferred is methyl.

Alkoxyalkyl is alkyl (which is preferably as just defined) that issubstituted at a carbon, preferably at a terminal carbon (inco-position), with an alkyloxy (=alkoxy) group wherein alkyl is asdefined above, preferably C₁-C₇-alkoxy. As alkoxyalkyl, 3-methoxypropylis especially preferred.

Protecting groups may be present (see also under “General ProcessConditions”) and should protect the functional groups concerned againstunwanted secondary reactions, such as acylation, etherification,esterifications, oxidations, solvolysis, and similar reactions. It is acharacteristic of protecting groups that they lend themselves readily,i.e. without undesired secondary reactions, to removal, typically bysolvolysis, reduction, photolysis or also by enzyme activity, forexample under conditions analogous to physiological conditions, and thatthey are not present in the end-products. The specialist knows, or caneasily establish, which protecting groups are suitable with thereactions mentioned hereinabove and hereinafter. Preferably, if two ormore protecting groups are present in one intermediate mentioned herein,they are chosen so that, if one of the groups needs to be removed, thiscan be done selectively, e.g. using two or more different protectinggroups that are cleavable under different conditions, e.g. one class bymild hydrolysis, the other by hydrolysis under harder conditions, oneclass by hydrolysis in the presence of an acid, the other by hydrolysisin the presence of a base, or one class by reductive cleavage (e.g. bycatalytic hydrogenation), the other by hydrolysis, or the like.

As hydroxyl protecting group, any group that is appropriate forreversible protection of hydroxy groups is possible, e.g. thosementioned in the standard textbooks under “General Process Conditions”.A hydroxyl protecting group may, just to mention a few examples, beselected from a group comprising (especially consisting of) a silylprotecting group, especially diaryl-lower alkyl-silyl, such asdiphenyl-tert-butylsilyl, or more preferably tri-lower alkylsilyl, suchas tert-butyldimethylsilyl or trimethylsilyl; an acyl group, e.g. loweralkanoyl, such as acetyl; benzoyl; lower alkoxycarbonyl, such astert-butoxycarbonyl (Boc), or phenyl-lower alkoxycarbonyl, such asbenzyloxycarbonyl; tetrahydropyranyl; unsubstituted or substituted1-phenyl-lower alkyl, such as benzyl or p-methoxybenzyl, andmethoxymethyl. Boc (selectively removable by hydrolysis) and benzyl(selectively removable by hydrogenation) are especially preferred.

As amino protecting group, any group that is appropriate for reversibleprotection of hydroxy groups is possible, e.g. those mentioned in thestandard textbooks under “General Process Conditions”. An aminoprotecting group may, just to mention a few examples, be selected from agroup comprising (especially consisting of) acyl (especially the residueof an organic carbonic acid bound via its carbonyl group or an organicsulfonic acid bound via its sulfonyl group), arylmethyl, etherifiedmercapto, 2-acyl-lower alk-1-enyl, silyl or N-loweralkylpyrrolidinylidene. Preferred amino-protecting groups are loweralkoxycarbonyl, especially tert-butoxycarbonyl (Boc), phenyl-loweralkoxycarbonyl, such as benzyloxycarbonyl, fluorenyl-loweralkoxycarbonyl, such as fluorenylmethoxycarbonyl, 2-tower alkanoyl-loweralk-1-en-2-yl and lower alkoxycarbonyl-tower alk-1-en-2-yl, with mostpreference being given to iso-butyryl, benzoyl, phenoxyacetyl,4-tert-butylphenoxyacetyl, N,N-dimethylformamidinyl,N-methylpyrrolidin-2-ylidene or especially tert-butoxycarbonyl.

A group X other than hydroxy or hydrogen is preferably a leaving group,e.g. halo, such as chloro, bromo or iodo, or the acyloxy moiety derivedfrom an organic sulfonic acid, such as a alkanesulfonyloxy, especiallyC₁-C₇-alkanesulfonyloxy, e.g. methanesulfonyloxy, haloalkanesulfonyloxy,especially halo-C1-C₇-alkanesulfonyloxy, such astrifluoromethane-sulfonyloxy, or unsubstituted or substitutedarylsulfonyloxy, such as toluolsulfonyloxy (tosyloxy).

Unsubstituted or substituted aryl is preferably a mono- or polycyclic,especially monocyclic, bicyclic or tricyclic aryl moiety with 6 to 22carbon atoms, especially phenyl (very preferred), naphthyl (verypreferred), indenyl, fluorenyl, acenapthytenyl, phenylenyl orphenanthryl, and is unsubstituted or substituted by one or more,especially one to three, moieties, preferably independently selectedfrom the group consisting of C₁-C₇-alkyl, C₁-C₇-alkenyl, C₁-C₇-alkynyl,halo-C₁-C₇-alkyl, such as trifluoromethyl, halo, especially fluoro,chloro, bromo or iodo, hydroxy, C₁-C₇-alkoxy, phenytoxy, naphthyloxy,phenyl- or naphthyl-C₁-C₇-alkoxy, C₁-C₇-alkanoyloxy, phenyl- ornaphthyl-C₁-C₇-alkanoyloxy, amino, mono- or di-(C₁-C₇-alkyl, phenyl,naphthyl, phenyl-C₁-C₇-alkyl, naphthyl-C₁-C₇-alkyl, C₁-C₇-alkarsoyland/or phenyl- or naphthyl-C₁-C₇-alkanoyl)-amino, carboxy,C₁-C₇-alkoxycarbonyl, phenoxycarbonyl, naphthyloxycarbonyl,phenyl-C₁-C₇-alkyloxycarbonyl, naphthyl-C₁-C₇-alkoxycarbonyl, carbamoyl,N-mono- or N,N-di-(C₁-C₇-alkyl, phenyl, naphthyl, phenyl-C₁-C₇-alkyland/or naphthyl-C₁-C₇-alkyl)-aminocarbonyl, cyano, sulfo, sulfamoyl,N-mono- or N,N-di-(C₁-C₇-alkyl, phenyl, naphthyl, phenyl-C₁-C₇-alkyland/or naphthyl-C₁-C₇-alkyl)-aminosulfonyl and nitro.

Salts are especially the pharmaceutically acceptable salts of compoundsof formula XV or generally salts of any of the intermediates mentionedherein, where salts are not excluded for chemical reasons the skilledperson will readily understand. They can be formed where salt forminggroups, such as basic or acidic groups are present that can exist indissociated form at least partially, e.g. in a pH range from 4 to 10 inaqueous solutions, or can be isolated especially in solid, especiallycrystalline, form.

Such salts are formed, for example, as acid addition salts, preferablywith organic or inorganic acids, from compounds of formula XV or any ofthe intermediates mentioned herein with a basic nitrogen atom (e.g.imino or amino), especially the pharmaceutically acceptable salts.Suitable inorganic acids are, for example, halogen acids, such ashydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organicacids are, for example, carboxylic, phosphonic, sulfonic or sulfamicacids, for example acetic acid, propionic acid, lactic acid, fumaricacid, succinic acid, citric acid, amino acids, such as glutamic acid oraspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid,benzoic acid, methane- or ethane-sulfonic acid, ethane-1,2-disulfonicacid, benzenesulfonic acid, 2-naphthalenesulfonic acid,1,5-naphthalene-disulfonic acid, N-cydohexylsulfamic acid, N-methyl-,N-ethyl- or N-propylsulfamic acid, or other organic protonic acids, suchas ascorbic acid.

In the presence of negatively charged radicals, such as carboxy orsulfo, salts may also be formed with bases, e.g. metal or ammoniumsalts, such as alkali metal or alkaline earth metal salts, for examplesodium, potassium, magnesium or calcium salts, or ammonium salts withammonia or suitable organic amines, such as tertiary monoamines, forexample triethylamine or tri(2-hydroxyethyl)amine, or heterocyclicbases, for example N-ethyl-piperidine or N,N′-dimethylpiperazine.

When a basic group and an acid group are present in the same molecule, acompound of formula XV or any of the intermediates mentioned herein mayalso form internal salts.

For isolation or purification purposes of compounds of the formula XV orin general for any of the intermediates mentioned herein it is alsopossible to use pharmaceutically unacceptable salts, for examplepicrates or perchlorates. For therapeutic use, only pharmaceuticallyacceptable salts or free compounds of the formula XV are employed (whereapplicable comprised in pharmaceutical preparations), and these aretherefore preferred at least in the case of compounds of the formula XV.

In view of the close relationship between the compounds andintermediates in free form and in the form of their salts, includingthose salts that can be used as intermediates, for example in thepurification or identification of the compounds or salts thereof, anyreference to “compounds”, “starting materials” and “intermediates”hereinbefore and hereinafter, especially to the compound(s) of theformula XV, is to be understood as referring also to one or more saltsthereof or a mixture of a corresponding free compound, intermediate orstarting material and one or more salts thereof, each of which isintended to include also any solvate, metabolic precursor such as esteror amide of the compound of formula XV, or salt of any one or more ofthese, as appropriate and expedient and if not explicitly mentionedotherwise. Different crystal forms may be obtainable and then are alsoincluded.

Where the plural form is used for compounds, starting materials,intermediates, salts, pharmaceutical preparations, diseases, disordersand the like, this is intended to mean one (preferred) or more singlecompound(s), salt(s), pharmaceutical preparation(s), disease(s),disorder(s) or the like, where the singular or the indefinite article(“a”, “an”) is used, this is not intended to exclude the plural, butonly preferably means “one”.

Starting materials are especially the compounds of the formula I, VI,XII and/or XXI mentioned herein, intermediates are especially compoundsof the formula III, IV, V, VII, VIII, IX, X, XI, XIII, XIV, XVI, XVII,XVIII, XIX, XX, XXI, XXIII and/or XXIV.

The invention relates also to methods of synthesis of the startingmaterials (e.g. of the formula I, VI, XII and/or XXI) and especially theintermediates of the formula III, IV, V, VII, VIII, IX, X, XI, XIII,XIV, XVI, XVII, XVIII, XIX, XX, XXI, XXIII and XXIV mentioned above fromtheir respective precursors as mentioned above, including methods withthe single steps of a sequence leading to a compound of the formula XV,more than one or all steps of said synthesis and/or pharmaceuticallyactive substances, especially renin inhibitors, most preferablyallskiren, including methods with the single steps of a sequence leadingto a compound of the formula XV, more than one or all steps of saidsynthesis and/or pharmaceutically active substances, and/or their use inthe synthesis of pharmaceutically active compounds, such as renininhibitors, especially allskiren.

General Process Conditions

The following, in accordance with the knowledge of a person skilled inthe art about possible limitations in the case of single reactions,applies in general to all processes mentioned hereinbefore andhereinafter, while reaction conditions specifically mentioned above orbelow are preferred:

In any of the reactions mentioned hereinbefore and hereinafter,protecting groups may be used where appropriate or desired, even if thisis not mentioned specifically, to protect functional groups that are notintended to take part in a given reaction, and they can be introducedand/or removed at appropriate or desired stages. Reactions comprisingthe use of protecting groups are therefore included as possible whereverreactions without specific mentioning of protection and/or deprotectionare described in this specification.

Within the scope of this disclosure only a readily removable group thatis not a constituent of the particular desired end product of formula XVis designated a “protecting group”, unless the context indicatesotherwise. The protection of functional groups by such protectinggroups, the protecting groups themselves, and the reactions appropriatefor their introduction and removal are described for example in standardreference works, such as J. F. W. McOmie, “Protective Groups in OrganicChemistry”, Plenum Press, London and New York 1973, in T. W. Greene andP. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition,Wiley, N.Y. 1999, in “The Peptides”; Volume 3 (editors: E. Gross and J.Meienhofer), Academic Press, London and New York 1981, in “Methoden derorganischen Chemie” (Methods of Organic Chemistry), Houben Weyl, 4thedition, Volume 15/l Georg Thieme Verlag, Stuttgart 1974, in H.-D.Jakubke and H. Jeschkeit, “Aminosauren, Peptide, Protelne” (Amino acids,Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basal1982, and in Jochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharideand Derivate” (Chemistry of Carbohydrates: Monosaccharides andDerivatives), Georg Thieme Verlag, Stuttgart 1974. A characteristic ofprotecting groups is that they can be removed readily (i.e. without theoccurrence of undesired secondary reactions) for example by solvolysis,reduction, photolysis or alternatively under physiological conditions(e.g. by enzymatic cleavage). Different protecting groups can beselected so that they can be removed selectively at different stepswhile other protecting groups remain intact. The correspondingalternatives can be selected readily by the person skilled in the artfrom those given in the standard reference works mentioned above or thedescription or the Examples given herein.

All the above-mentioned process steps can be carried out under reactionconditions that are known per se, preferably those mentionedspecifically, in the absence or, customarily, in the presence ofsolvents or diluents, preferably solvents or diluents that are inerttowards the reagents used and dissolve them, in the absence or presenceof catalysts, condensation or neutralizing agents, for example ionexchangers, such as cation exchangers, e.g. in the H* form, depending onthe nature of the reaction and/or of the reactants at reduced, normal orelevated temperature, for example in a temperature range of from about−100° C. to about 190° C., preferably from approximately −80° C. toapproximately 150° C., for example at from −80 to −60° C., at roomtemperature, at from −20 to 40° C. or at reflux temperature; underatmospheric pressure or in a closed vessel, where appropriate underpressure, and/or in an inert atmosphere, for example under an argon ornitrogen atmosphere.

The solvents from which those solvents that are suitable for anyparticular reaction may be selected include those mentioned specificallyor, for example, water, esters, such as lower alkyl-lower alkanoates,for example ethyl acetate, ethers, such as aliphatic ethers, for examplediethyl ether, or cyclic ethers, for example tetrahydrofurane ordioxane, liquid aromatic hydrocarbons, such as benzene or toluene,alcohols, such as methanol, ethanol or 1- or 2-propanol, nitrites, suchas acetonitrile, halogenated hydrocarbons, e.g. as methylene chloride orchloroform, acid amides, such as dimethylformamide or dimethylacetamide, bases, such as heterocyclic nitrogen bases, for examplepyridine or N-methylpyrrolidin-2-one, carboxylic acid anhydrides, suchas lower alkanoic acid anhydrides, for example acetic anhydride, cyclic,linear or branched hydrocarbons, such as cyclohexane, hexane orisopentane, or mixtures of these, for example aqueous solutions, unlessotherwise indicated in the description of the processes. Such solventmixtures may also be used in working up, for example by chromatographyor partitioning. Where required or desired, water-free or absolutesolvents can be used.

Where required, the working-up of reaction mixtures, especially in orderto isolate desired compounds or intermediates, follows customaryprocedures and steps, e.g. selected from the group comprising but notlimited to extraction, neutralization, crystallization, chromatography,evaporation, drying, filtration, centrifugation and the like.

The invention relates also to those forms of the process in which acompound obtainable as intermediate at any stage of the process is usedas starting material and the remaining process steps are carried out, orin which a starting material is formed under the reaction conditions oris used in the form of a derivative, for example in protected form or inthe form of a salt, or a compound obtainable by the process according tothe invention is produced under the process conditions and processedfurther in situ. In the process of the present invention those startingmaterials are preferably used which result in compounds of formulaXV-scribed as being preferred. Special preference is given to reactionconditions that are identical or analogous to those mentioned in theExamples. The invention relates also to novel starting compounds andintermediates described herein, especially those leading to compoundsmentioned as preferred herein.

The invention especially relates to any of the methods describedhereinbefore and hereinafter that leads to allskiren, or apharmaceutically acceptable salt thereof.

The following Examples serve to illustrate the invention withoutlimiting the scope thereof, while they on the other hand representpreferred embodiments of the reaction steps, intermediates and/or theprocess of manufacture of allskiren, or salts thereof.

Where mentioned in the Examples, “boc” stands for tert-butoxycarbonyl.

Examples I. Synthesis of (1S, 3S,6S)-6-tert-Butoxycarbonyloxymethyl-3-isopropyl-2-[4-methoxy-3-(3-methoxy-propoxy)-phenyl]pyrrolidine-1-carboxylicadd tert-butyl ester 3

-   -   A Variant employing thionyl chloride: A solution of 2.16 g of        carbonic acid (2S,        4S)-2-tert-butoxycarbonylamino-4-[4-methoxy-3-(4-methoxy-butyl)-benzyl]5-methyl-hexyl        ester tert-butyl ester 1 in 30 mL of dry toluene is treated with        1.07 g of pyridine and 0.68 g of thionyl chloride is added        dropwise at room temperature. The mixture is stirred at room        temperature for 3 hours and 0.22 g of ethanol and 30 mL of water        are added. The two phase system is extracted and the organic        layer removed and washed with 20 mL of 10% aqueous sodium        hydrogen sulphate solution followed by 20 mL of saturated        aqueous sodium bicarbonate solution. Finally the organic phase        is washed twice with 20 mL of water and the solvent removed in        vacuum to give an oil. Chromatography on silica-gel, eluting        with heptane/ethyl acetate mixtures provides e.g. 1.04 g of 3 as        an oil with a negative [a]_(d) (measured: e.g. −39.1) at c=1,        CHCl₃.

-   -   B Variant employing methanesulfonyl chloride: A solution of 1.98        g of carbonic acid (2S,        4S)-2-tertbutoxycarbonylamino-4-[4-methoxy-3-(4-methoxy-butyl)benzyl]5-methyl-hexyl        ester tert butyl ester 1 in 20 mL of dry toluene is treated with        0.044 g of dimethylaminopyridine and 0.55 g of triethylamine and        cooled to 0° C. Methanesulphonyl chloride (0.43 g) is added        dropwise and the reaction mixture is warmed to room temperature        and stirred for 30 hours. The mixture is diluted with 20 mL of        water and the organic layer separated. The organic layer is        washed with 20 mL of saturated aqueous sodium bicarbonate        solution and finally the organic phase is washed twice with 20        mL of water and the solvent removed in vacuum to give an oil.        Chromatography on silica-gel, eluting with heptane/ethyl acetate        mixtures provides e.g. 1.64 g of 3 as an oil. The product shows        a negative (aid (measured: e.g. −39.1) at c=1. CHCl₃.    -   C Variant employing triphenylphosphine/iodine: A solution of        1.46 g of carbonic acid (2S,        4S)-2-tertbutoxycarbonylamino-4-[4-methoxy-3-(4-methoxy-butyl)-benzyl]5-methyl-hexyl        ester tert butyl ester 1 in 15 mL of dry toluene/acetonitrile        (85/15) is treated with 0.58 g of imidazole at room temperature.        Triphenylphosphine (1.14 g) is added, followed by dropwise        addition of a solution of 1.119 of iodine in 15 Ml of        toluene/acetonitrile (85/15) within 15 minutes. The reaction        mixture is stirred at room temperature for 4 hours and quenched        with 20mL of a 5% solution of sodium thiosulphate. The organic        phase is separated and washed twice with 20 mL of brine. The        solvent is removed under vacuum and the resulting oil is        chromatographed on silica-gel to give e.g. 1.24 g of 3 as an        oil.    -   D Variant employing ion exchange resin:

45.70 g of carbonic acid (2S,4S)-2-tertbutoxycarbonylamino-4-[4-methoxy-3-(4-methoxy-butyl)-benzyl)5-methyl-hexylester tert butyl ester 1 (HPLC 95.0% b.a., 78.1 mmol) are at r.t.dissolved in 390 ml of acetonitrile. To the solution are added 11.6 g(55.0 mequ) Amberlyst 15 (Fluke 06423, 4.7 mequ/g). The resultingmixture is stirred at r.t. for 5 hours. Then filtration and evaporationof the filtrate at 50° C. and 20 mbar afford the residue as a dearcolourless oil. Purity HPLC 97,2% b.a.

The starting material 1 can be prepared according to the followingmethod:

Preparation of compound 1 by reduction of the corresp. aryl ketone withLiBH₄

In a 350 ml three necked flask are dissolved 34.5 g (62.3 mmol) ofbis-Boc-aryl ketone in 400 ml of ethanol and 3.5 ml of water. To thissolution is added a solution of 40.7 g of LiBH₄ in 32 ml of THF via adropping funnel within 15 min. at room temperature. The dropping funnelis rinsed with 8 ml of THE and the reaction mixture is stirred at roomtemperature over night. Then an additional amount of 13.6 g of LiBH₄ ina mixture of 10 ml THE and 1 ml of water is added. The reaction mixtureis warmed to 40° C. for 2 hours and is then cooled to 0° C. The reactionis quenched with 125 ml acetic acid followed by an extractive work upwith 500 ml of water and 500 ml of TBME. The organic phase is dried viasodium sulfate and evaporated in vacuum to give a very viscous oil whichconsist as a mixture of epimeric benzylic alcohols in the ratio (8:1).

II. Synthesis of (2R, 3S,5S)-5-Hydroxymethyl-3-isopropyl-2-[4-methoxy-3-(3-methoxy-propoxy)-phenyl]pyrrolidine-1-carboxylicacid tert-butyl ester 6

A solution of 2.52 g pyrrolidine 3 in 2.5 mL of methanol is treated with3.87 g of potassium carbonate, and the suspension is warmed to 45° C.and stirred at this temperature for 4 hours. The reaction is thendiluted with 60 mL of tert-butylmethyl ether and 20 mL of water and themixture extracted. The organic layer is separated and the aqueous layeris washed with a further charge of 40 mL of tert-butylmethyl ether. Thecombined organic layers are washed twice with 20 mL of water and thesolvent is removed in vacuum to give the alcohol 6 as an oil. A negative[a]_(d) is found at c=1, CHCl₃. ¹H-NMR (d⁶-DMSO/D₂O, 300K)6.90-6.80(3H), 4.03-3.90(3H), 3.80(1H), 3.75(3H), 3.55-3.45(3H),3.23(3H), 3.05(1H), 2.00-1.80(3H), 1.65(1H), 1.40(9H), 1.20(1H),0.74(6H).

Alternative route to (2R,3S,5S)-5-1-Hydroxymethyl-3-isopropyl-2-[4-methoxy-3-(3methoxy-propoxy)-phenyl]pyrrolidine-1-carboxylic acid tert-butyl ester 6

Synthesis of [(2S, 5R, 5R)-4-isopropyl5-554-methoxy-3-methoxy-propoxy)-phenyl]-pyrrolidin-2-yl}-methanol(Z)-but-2-enedioic acid 1/salt 6

To a solution of 5.56 g of carbonic acid (2S,4S)-2-tertbutoxycarbonylamino-4-(4-methoxy-3-(4-methoxy-butyl)-benzyl]5-methyl-hexylester tert-butyl ester (1) in 28 ml ethanol absolute, 2.5 ml of aqueoushydrochloric acid 37% (or an equivalent amount of hydrochiorid acid inethanol 2 M) is added at 0-5° C. After stirring for 1 h at 0-5° C., thereaction mixture is gradually heated to 78-80° C. within 1 h. Stirringat reflux temperature is continued for 2-4 h, until transformation iscomplete. The reaction mixture is cooled to RT, and 18 ml of water isadded. The organic solvent (ethanol) is stripped off in vacuo, and theremaining aqueous concentrate is extracted with 12 ml isopropylacetate.The aqueous layer is separated, and after addition of 30 mlisopropylacetate, approximately 3.2 ml aqueous sodium hydroxid solution30% is slowly added at 0-5° C. under vigorous agitation, until pH 11-12is reached. The organic layer is separated and concentrated toapproximately 25 ml residual volume (azeotropic removal of remainingwater).

A solution of 1.16 g maleic acid in 12 ml isopropanol is added to theconcentrate of intermediate (5) free base in isopropylacetate at 40° C.Crystallization of (5) maleate is initiated by seeding at 40° C. andcompleted by cooling of the suspension to 0-5° C. The crystalline (5)maleate 1/1 salt is collected by filtration, washed with 16 mlisopropylacetate/isopropanol 3/1 (v) and dried in vacuo. ¹H-NMR(d⁶-DMSO, 300 K : 7.2 (1H), 6.9-7.1 (2H), 6.0 (2H), 5.3 (1H), 4.1-4.2(1H), 3.9-4.1 (2H), 3.8 (1H), 3.6-3.7 (3H), 3.4-3.5 (2H). 3.3 (3H),2.4-2.5 (1H), 1.9-2.0 (3H), 1.8-1.9 (1H), 1.6-1.7 (1H), 0.8-0.9 (3H),0.7-0.8 (3H).

Synthesis of (2R, 3S,5S)-5-Hydroxymethyl-3-isopropyl-2-[4-methoxy-3-(3-methoxy-propoxy)-phenyl]-pyrrolidine-1-carboxylicacid tert-butyl ester (6)

2.27 g (5) maleate 1/1 salt is dissolved in a mixture of 10 mlmethylenechloride and 8 ml water. 8 ml aqueous sodium hydroxide solution2.0 M is added at 0-5° C. under vigorous stirring. Then a solution of1.14 g di-tert-butyl-dicarbonate in 10 ml methylene chloride is addedwithin 10 min. After 15 min at 0-5° C., the reaction mixture is slowlyheated to room temperature and further agitated for approximately 0.5 h.

The organic phase is separated, washed with water, dried over sodiumsulfate or by azeotropic destination and finally evaporated in vacuo.The remaining crude (6)—or a concentrate of the product inmethylenechloride—can be directly further processed to (7) according topatent example below.

III. Synthesis of (2R, 3S, 5S)-5-Formyl-3-isopropyl-2-[4-methoxy-3-(3methoxy-propoxy)-phenyl]-1-carboxylic acid tert-butyl ester 7

Using SO₃/pyridine complex: A solution of 4.7 g of alcohol 6 in 58 m ofmethylene chloride is treated with 33 mL of dimethylsulphoxide and 5.67g of triethylamine is added. The mixture is cooled to 0° C. and asolution of 6.84 g of the SO₃/pyridine complex dissolved in 46 mL ofdimethyl Sulphoxide is added dropwise within 20 minutes. The reaction isstirred at 0° C. for 2 hours and quenched with 105 mL of water and 105mL of heptane. The organic layer is separated and washed with 25 mL of10% aquoeus sodium hydrogen sulphate solution. The organic phase is thenwashed with 110 mL of water followed by 25 mL of saturated aqueoussodium hydrogen carbonate solution. Finally the organic phase is washedwith water until the pH of the aqueous solution is 7. The solvent isthen removed to give the aldehyde 7 as an oil. A negative [a]_(d) isfound at c=1, CHCl₃. ¹H-NMR (d⁶-DMSO, 300K) 9.75(1H), 6.90-6.80(3H),4.63-4.30(3H), 4.00(2H), 3.75(3H), 3.50(3H), 3.23(3H), 2.10-1.90(4H),1.85(1H), 1.60(1H), 1.05(9H). 0.85(6H).

Alternatively, to a solution of 1.1 g of the alcohol 6 in 10 mL ofdichloromethane is added 0.4 g of pyridine, 1.1 g ofdiisopropylethylamine and 2.0 g of dimethyl sulfoxide. The mixture iscooled to −5° C. and 0.6 g of sulfur trioxide-pyridine complex is addedin four portions over a period of 2 h. The reaction is quenched byaddition of 2.5 mL of water and acidified by addition of 1 mL of 37%hydrochloric acid. The phases are separated and the organic phase washedwith 2.5 mL of water, dried over sodium sulfate and the solvent removedin-vacuum, to afford e.g. 0.88 g of the aldehyde 7 as an oil.

Using TEMPO: A mixture of 0.96 g of the alcohol 6, 0.044 g of sodiumhydrogencarbonate, 0.026 g of potassium bromide and 0.051 g of TEMPO in3 mL of dichloromethane and 1.2 mL of water is cooled to 5° C. To themixture is added dropwise 0.13 g of 10-13% sodium hypochlorite solution,and the mixture stirred for 5 h between 5° C. and 20° C., beforeaddition of 0.57 g of sodium sulfite. The phases are then separated andthe organic phase washed twice with 5 mL of water. Evaporation of thesolvent in vacuum affords e.g. 0.50 g of the aldehyde 7 as an oil.

IV. Synthesis of (2R, 3S, 5S)-4-isopropyl-5-[4-methoxy-3-(3methoxy-propoxy)-phenyl]pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester 15

A solution of 1.7 g of the aldehyde 7 in 15 mL of tert-butanol istreated with 3 mL of 2-methyl-2-butene. A solution of 0.43 g of sodiumchlorite and 1.73 g of sodium dihydrogen phosphate in 15 mL of water isadded dropwise. The two phase mixture is stirred for 90 minutes at roomtemperature and 15 mL of toluene and 15 mL of water is added. Theorganic layer is separated and washed with 20 mL of water. The solventis removed in vacuum to give the acid 15 as a clear oil which slowlycrystallizes. ¹H-NMR (d⁸-DMSO, 354K) 12.25(1H), 7.35(1H), 6.90(1H),6.81(1H), 4.38(1H), 4.25(1H), 4.00(2H), 3.75(3H), 3.45(2H), 3.23(3H),2.15-1.85(48), 1.65(1H), 1.25(98), 0.85(6H).

V. Synthesis of (2R, 3S, 5S)-5-((1S,3S)-3-Benzoyloxymethyl-1-hydroxy-4-methyl-phenyl)-3-isopropyl-2-[4-methoxy-3-(3methoxy-propoxy)-phenyl]pyrrolidine-1-carboxylic acid tert-butyl ester B

A solution of 1.98 g of aldehyde 7 in 15 mL of tetrahydrofuran is cooledto 10° C. and is treated with the Grignard reagent prepared by treating1.23 g of ((S)-2-bromomethyl-3-methyl-butoxymethyl)-benzene with 0.12 gof magnesium in diethylether containing 0.043 g of 1,2-dibromoethane at45° C. The reaction is stirred for 90 minutes at room temperature, then20 mL of a 25% aqueous solution of ammonium chloride is added, followed,by addition of 20 mL of tert-butylmethyl ether. The organic phase isseparated and washed twice with 20 mL of water. The organic phase isconcentrated in vacuum to give the crude alcohol 8 as an oil.Purification on silica-gel delivers e.g. 0.979 of pure 8. A negative[a]_(d) is found at c=1, CHCl₃. M⁺+H=628, M⁺+H+Na=650.

Alternatively, A solution of 27 g of aldehyde 7 in 30 mL oftetrahydrofuran is added to a room-temperature solution of the Grignardreagent prepared by refluxing 20 g of((S)-2-chloromethyl-3-methyl-butoxymethyl)-benzene with 3.2 g ofmagnesium in 120 mL of tetrahydrofuran containing 1.3 g of1,2-dibromoethane for 4 h. The reaction is stirred for 1 h at roomtemperature, then 100 mL of 2 N sulfuric acid is added. The mixture isstirred until the excess magnesium has dissolved, then the phases areseparated and the organic phase washed with 50 mL of 12% sodium chloridesolution. The organic phase is concentrated in vacuum to give e.g. 42.6g of the crude alcohol 8 as an oil.

VI Synthesis of (2R, 3S, 5S)-5-((1S,3S)-1-Hydroxymethyl-3-hydroxymethyl-4-methylpentyl)-3-isopropyl-2-[4-methoxy-3-(3methoxy-propoxy)-phenyl]pyrrolidine-1-carboxylic acid tert-butyl ester 9

A solution of 0.48 g of 8 in 1.5 mL of methanol is treated with 0.19 of10% palladium on charcoal. The suspension is stirred under an atmosphereof hydrogen until the uptake is stable. The suspension is filtered andthe solid washed with 5 mL of methanol in two portions. Removal of thesolvent in vacuum provides alcohol 9 as an oil. A negative [a]_(d) (e.g.−34.1, −34.6) is found at c=1. CHCl₃.

VIa. Synthesis of((1S,2S,4S)-2-Hydroxy-4-hydroxymethyl-1-[(S)-2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl]-5-methyl-hexyl)-carbamicacid tert-butyl ester 9a

a) A solution of 1 g of the pyrrolidine 8 in 17 mL of THF is cooled to−78° C. and 17 mL of ammonia condensed into the flask. To the mixture isadded 0.44 g of Sodium and the resulting dark-coloured mixture stirredover night at −78° C. To the mixture is added 2.6 g of ammoniumchloride. The mixture is allowed to warm to r.t. (ammonia evaporates offand unreacted sodium is dissolved) before addition of 40 mL of tolueneand 1.9 g of acetic acid. After 10 min 25 mL of water is added and thephases are separated. The aqueous phase is back-extracted with 25 mL oftoluene, then the combined organic phases are washed four times with 1:1water-brine before drying over sodium sulfate and evaporating in vacuum.Purification of the crude oily product (0.86 g) on silica get, elutingwith ethyl acetate-heptane affords e.g. 0.71 g of pure 9a. ¹H-NMR(CDCl₃, 300k): 6.8 (2H), 6.7 (1H), 4.7 (1H), 4.1 (2H), 3.8 (3H), 3.5-3.7(5H), 3.4-3.5 (1H), 3.4 (3H), 2.7-2.8 (1H), 2.4-2.5 (3H), 2.0-2.2 (2H),1.5-1.8 (8N), 1.4 (9H), 0.8-0.9 (12H).

b) A solution of 1.0 g of the pyrrolidine 8 in 2.5 mL of tetrahydrofuranis added to a mixture of 0.37 g of sodium in 5 mL of ammonia and 2.5 mLof tetrahydrofuran at −50° C. The mixture is stirred for 3 h then 2.56 gof ammonium chloride is added and the mixture allowed to warm to r.t. Tothe mixture is then added 40 mL of toluene, 1.9 g of acetic acid and 25mL of water. The phases are separated and the aqueous phase isback-extracted with 25 mL of toluene. The combined organic phases arethen washed with 4×120 mL of 1:1 water-brine, dried over sodium sulfateand the solvent removed in vacuum, affording e.g. 0.76 g of the product9a as an oil.

VII. Synthesis of (2R, 3S, 5S)-5-((2S,4S)-5-Hydroxy-4-isopropyl-tetrahydro-furan-2yl)-3-isopropyl-2-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-pyrolidine-1-carboxylicacid tert-butyl ester 10

Variant employing SO₃/pyridine: A solution of 0.20 g of alcohol 9 in 5mL of methylene chloride is treated with 3 mL of dimethyl sulphoxide and0.2 g of triethylamine at 0° C. A solution of 0.24 g of the SO₃/pyridinecomplex in 4 mL of dimethyl sulphoxide is added dropwise within 15minutes at 0° C. The reaction is stirred for 40 minutes at 0° C. thenwarmed to room temperature and stirred for a further 2 hours.

Water (10 mL) and heptane (15 mL) are added, and the resulting mixtureis extracted. The organic phase is washed with 15 mL of a 10% aqueoussolution of sodium hydrogen sulphate followed by water (15 mL) and 10%aqueous sodium bicarbonate solution. The organic phase is removed invacuum to give e.g. 0.189 of the lactol 10 M⁺+=536.

VIII. Synthesis of (2R, 3S, 5S)-3-isopropyl-5-((2S,4S)-4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-3-isopropyl-2-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-pyrolidine-1-carboxylicacid tert-butyl ester 11

A solution of 0.16 g of alcohol 9 in 3 mL of methylene chloride istreated with 0.005 g of TEMPO followed by portionwise addition of 0.20 gof (diacetoxyiodo)benzene. The mixture is stirred for 5 hours at roomtemperature after which time only lactol 10 can be detected. A further0.20 g of diacetoxyiodo benzene is added and the reaction stirred for afurther 24 hours at room temperature. Aqueous sodium thiosulphatesolution (5 mL of 10%) and water (5 mL) are added and the phases areseparated. The organic phase is washed with 10 mL of water and thesolvent is removed in vacuum to give an oil. Chromatography onsilica-gel gives e.g. 0.12 g of 11. [α]_(D)=+28.3° (1%, CHCl₃), mp.:70-71.5° C., ¹H-NMR (CDCl₃, 300K): 6.6-6.8 (3H), 4.3-4.4 (2H), 4.0-4.1(2H), 3.7-3.8 (4H), 3.5-3.6 (2H), 3.3 (3H), 2.5-2.6 (2H), 2.3-2.4 (1H),2.0-2.2 (5H), 1.4-1.7 (4H), 1.4 (9H), 1.0 (3H), 0.9 (3H), 0.8 (6H).

Alternatively, 76 mg of lactol 10 are dissolved in 2 ml of acetonitrileand 80 mg of molecular sieve is added. To the suspension is added asolution of 21 mg of N-methylmorpholine N-oxide and 2.5 mg of TPAP(tetra-N-propylammonium perruthenate) in 1 ml of acetonitrile. After 2hours stirring at room temperature the reaction is complete. The solventis evaporated in vacuum and the residue is dissolved in ethyl acetateand filtered via a short pad if silicagel. The filtrate is evaporated invacuum to give 77 mg of compound 11.

Alternatively, to a solution of 0.68 g of the alcohol 9a in 18 mL ofacetonitrile, containing 0.7 g of 4Å powdered molecular sieves, is added0.59 g of N-methylmorpholine-N-oxide and 44 mg of tetrapropylammoniumperruthenate, and the mixture is stirred overnight. After removal of thesolvent in vacuum, the residue is taken up in ethyl acetate, filteredthrough silica gel, washing with ethyl acetate, and the solvent againremoved in vacuum. Purification of the crude oily product (0.72 g) onsilica gel, eluting with ethyl acetate-heptane affords e.g. 0.57 g ofthe pure Lactone 11.

IX. Synthesis of(2R,3S,5S)-5-[(1S,3S)-3-(2-carbamoyl-2-methyl-propylcarbamoyl)-1-hydroxy-4-methyl-phenyl]-3-isopropyl-2-4-methoxy-3-(3-methoxy-phenyl]-pyrolidine-1-carboxylicacid tert-butyl ester 12

A solution of 0.08 g of lactone 11, 0.052 g of3-amino-2,2-dimethylpropionamide and 0.014 g of 2-hydroxypyridine in 0.3mL of tert-butylmethyl ether containing 0.02 g of triethylamine isstirred for 18 hours at 83° C. The reaction mixture is then cooled toroom temperature and diluted with 2 mL of toluene and washed with 2 mLof 10% aqueous sodium hydrogen sulphate solution. The organic phase isseparated and washed with water, and the solvent is removed in vacuum togive an oil. This oil is suspended in 5 mL of hexane and stirred. Thesolid is removed by filtration and the hexane removed in vacuum to givee.g. 0.06 g of amide 12 as a foam. M⁺−H=648.

X. Synthesis of ((1S, 2S,4S)-4-(2-carbamoyl-2-methyl-propylcarbamoyl)-2-hydroxy-1-{(S)-2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methylbutyl}-5-methyl-hexyl)-carbamicacid tert-butyl ester 13

A solution of 0.037 g of amide 12 is dissolved in 1 mL oftetrahydrofurane and cooled to −78° C. Liquid ammonia is added followedby 0.0042 g of lithium metal. The deep blue solution is stirred for 2hours at −78° C., and then 0.35 g of ethanol is added and the mixture isstirred for 30 minutes at −78° C. Ammonium chloride (0.15 g) is addedand the mixture is warmed to room temperature. The organic phase ispartitioned between water and ethyl acetate. The organic phase isseparated and the solvent removed in vacuum. The residue is stirred withheptane and filtered. Removal of the heptane produces 13 identical withan authentic sample. M⁺+H=652

XI.(2S,4S,5S,7S)-5-amino-N-[2-carbamoyl-2-methylpropyl)-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnonanamide)

Product 13 is dissolved in a mixture of 4.0M hydrochloric acid indioxane. The solution is stirred for 24 hours at room temperature andneutralized with solid sodium bicarbonate. The suspension is filteredand the solvent removed in vacuum to give the product as a foam (forcharacterization see e.g. EP 0 678 503. Example 137).

From the free compound or the hydrochloride salt obtainable, for examplethe hemifumarate salt of the title compound can be prepared, for exampleas described in U.S. Pat. No. 6,730,798, example J1 (comprising mixingwith fumaric acid, dissolution in ethanol, filtration, evaporation ofthe obtained solution, re-dissolving of the residue in acetonitrile,inoculation with a small amount of the title compound's hemifumaratesalt and isolation of the precipitating material), incorporated byreference herein especially with regard to this salt formation reaction.

1-2. (canceled)
 3. A compound of the formula III

wherein R is hydrogen, alkyl or alkoxyalkyl, preferably C₁-C₇-alkoxy,especially methoxy; R₁ is hydrogen, alkyl or alkoxyalkyl,C₁-C₇-alkoxy-C₁-C_(c)-alkyl, especially 3-methoxypropyl; R₂ is hydrogenor preferably a hydroxyl protecting group; R₃ is hydrogen orunsubstituted or substituted alkyl; and PG is an amino protecting group,especially one removable by hydrolysis, e.g. lower alkoxycarbonyl, suchas tert-butoxycarbonyl; or a salt thereof.
 4. A compound of the formulaI

wherein R, R₁,R₂,R₃ and PG are as defined in claim 3 preferably whereinthe compound of formula I is (1S, 3S,5S)-5-tert-butoxycarbonyloxymethyl-3-isopropyl-2-[4-methoxy-3-(3-methoxy-propoxy)-phenyl]pyrrolidine-1-carboxylicacid tert-butyl ester, or a salt thereof.
 5. A process for themanufacture of a compound of the formula IV,

wherein R, R₁, R₃ and PG are as defined under formula III in claim 3 ora salt thereof, comprising removing a hydroxy protecting group R₂ in acompound of the formula III, or a salt thereof.
 6. A compound of theformula IV,

wherein R, R₁, R₂, R₃, and PG are as defined in claim 3; or a saltthereof.
 7. A compound of the formula IV according to claim 5 with thename (2R, 3S, 5S)-5-hydroxymethyl-3-isopropyl-2-[4-methoxy-3-(3methoxy-propoxy)-phenyl]pyrrolidine-1-carboxylic acid tert-butyl ester,or a salt thereof.
 8. A process for the manufacture of a compound of theformula IVa,

wherein R, R₁, R₂, R₃ and PG are as defined in claim 3; or a saltthereof; said process comprising removing a protecting groups R₂ and PGin a compound of the formula I, or a salt thereof and to form thepyrrolidine ring,

wherein R, R₁, R₂ and R₃ are as defined for a compound of the formulaIII and PG is an amino protecting group, especially one removable byhydrolysis, e.g. lower alkoxycarbonyl, such as tert-butoxycarbonyl orbenzyloxycarbonyl.
 9. A process for the manufacture of a compound of theformula IV,

wherein R, R₁, R₂, R₃ and PG are as defined in claim 3; or a saltthereof; said process comprising protecting the a pyrrolidine nitrogenwith a protecting weeps group PG in a compound of the formula (IVa), ora salt thereof

wherein R, R₁, R₂ and R₃ are as defined for a compound of the formulaIII.
 10. A process for the manufacture of an oxo compound of the formulaV.

wherein R, R₁, R₃ and PG are as defined under formula III in claim 3, ora salt thereof, comprising oxidizing a compound of the formula IV, or asalt thereof, where in the case that R₃ in a compound of the formula IVis hydrogen the oxidation can take place directly to the oxo compound ofthe formula V or by oxidizing first to an acid of the formula XVI

wherein R, R₁ and PG are as defined above for a compound of the formulaV, or a salt thereof, which is then reduced with a reducing agent to thecorresponding aldehyde of the formula V wherein R₃ is hydrogen and theother moieties are as mentioned above.
 11. A compound of the formula XVIaccording to claim 10, wherein R is hydrogen, alkyl or alkoxyalkyl,preferably C₁-C₁-alkoxy, especially methoxy; R₁ is hydrogen, alkyl oralkoxyalkyl, C₁-C₇-alkoxy-C₁-C₇alkyl, especially 3-methoxypropyl; and PGis an amino protecting group, or a salt thereof.
 12. A compound of theformula XVI according to claim 11 with the name (2R, 3S,5S)-4-isopropyl-5-[4-methoxy-3-(3methoxy-propoxy)-phenyl]pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester, or a salt thereof.
 13. A compound of the formula V according toclaim 10, wherein R is hydrogen, alkyl or alkoxyalkyl, preferablyC₁-C₇-alkoxy, especially methoxy; R₁ is hydrogen, alkyl or alkoxyalkyl,C₁-C₇-alkoxy-C₁-C₇-alkyl, especially 3-methoxypropyl; R₃ is hydrogen orunsubstituted or substituted alkyl; and PG is an amino protecting group,especially one removable by hydrolysis, e.g. lower alkoxycarbonyl, suchas tert-butoxycarbonyl; or a salt thereof.
 14. A compound of the formulaV according to claim 13, wherein the compound is (2R, 3S,5S)-5-formyl-3-isopropyl-2-[4-methoxy-3-(3methoxy-propoxy)-phenyl]pyrrolidine-1-carboxylic acid tert-butyl ester,or a salt thereof.
 15. A process for the manufacture of a compound ofthe formula VII,

wherein R, R₁ and PG are as defined under formula III in claim 3 and PTis a hydroxyl protecting group, comprising reacting a compound of theformula V, wherein R is hydrogen, alkyl or alkoxyalkyl, preferablyC₁-C₇-alkoxy, especially methoxy; R₁ is hydrogen, alkyl or alkoxyalkyl,C₁-C₇-alkoxy-C₁-C_(c)-alkyl, especially 3-methoxypropyl; R₃ is hydrogen;and PG is an amino protecting group, especially one removable byhydrolysis, e.g. lower alkoxycarbonyl, such as tert-butoxycarbonyl; or asalt thereof under Grignard or Grignard-like conditions with a reagentprepared by reaction of a compound of the formula VI,

wherein Hal is halo and PT is a hydroxyl protecting group, with a metal.16. A compound of the formula VII according to claim 15 wherein R ishydrogen, alkyl or alkoxyalkyl, preferably C₁-C₇-alkoxy, especiallymethoxy; R₁ is hydrogen, alkyl or alkoxyalkyl,C₁-C₇-alkoxy-C₁-C_(c)-alkyl, especially 3-methoxypropyl; R₃ is hydrogen;and PG is an amino protecting group, especially one removable byhydrolysis, e.g. lower alkoxycarbonyl, such as tert-butoxycarbonyl; or asalt thereof.
 17. A compound of the formula VII according to claim 16wherein the compound is (2R, 3S, 5S)-5-((1S,3S)-3-Benzoyloxymethyl-1-hydroxy-4-methyl-pentyl)-3-isopropyl-2-[4-methoxy-3-(3methoxy-propoxy)-phenyl]pyrrolidine-1-carboxylic acid tert-butyl ester,or a salt thereof.
 18. A process for the manufacture of a compound ofthe formula VIII,

wherein R, R₁ and PG are as defined for a compound of the formula III inclaim 3, or a salt thereof, comprising deprotecting a compound of theformula VII under removal of the hydroxy protecting group PT.
 19. Acompound of the formula VIII according to claim 18, or a salt thereof,wherein R is hydrogen, alkyl or alkoxyalkyl, preferably C₁-C₇-alkoxy,especially methoxy; R₁ is hydrogen, alkyl or alkoxyalkyl,C₁-C₇-alkoxy-C₁-C_(c)-alkyl, especially 3-methoxypropyl; and PG is anamino protecting group, or a salt thereof.
 20. A compound of the formulaVIII according to claim 19, wherein the compound is (2R, 3S, 5S)-5-((1S,3S)-1-hydroxymethyl-3-hydroxymethyl-4-methylpentyl)-3-isopropyl-2-[4-methoxy-3-(3methoxy-propoxy)-phenyl]pyrrolidine-1-carboxylic acid tert-butyl ester,or a salt thereof.
 21. A process for the manufacture of a lactol of theformula X,

wherein R₁, R and PG are as defined for a compound of the formula III inclaim 3, or a salt thereof, comprising oxidizing a compound of theformula VIII, or a salt thereof, at the primary hydroxy group to analdehyde compound of the formula IX,

wherein R, R₁ and PG are as defined under formula X above, or a saltthereof, which then cyclizes spontaneously to produce a lactol of theformula X, or a salt thereof.
 22. A lactol of the formula X according toclaim 21, or a pharmaceutically acceptable salt thereof, wherein R ishydrogen, alkyl or alkoxyalkyl, preferably C₁-C₇alkoxy, especiallymethoxy; R₁ is hydrogen, alkyl or alkoxyalkyl,C₁-C₇-alkoxy-C₁-C_(c)-alkyl, especially 3-methoxypropyl; and PG is anamino protecting group, or a salt thereof.
 23. A lactol of the formula Xaccording to claim 22, wherein the compound is (2R, 3S, 5S)-6-((2S,4S)-5-hydroxy-4-isopropyl-tetrahydra-furan-2-yl)-3-isopropyl-2-[4-methoxy-3-(3-methoxypropoxy)-phenyl[-pyrolidine-1-carboxylicacid tert-butyl ester, or a salt thereof.
 24. An aldehyde compound ofthe formula IX according to claim 21, or a pharmaceutically acceptablesalt thereof, wherein R is hydrogen, alkyl or alkoxyalkyl, preferablyC₁-C₇-alkoxy, especially methoxy; R₁ is hydrogen, alkyl or alkoxyalkyl,C₁-C₇-alkoxy-C₁-C_(c)-alkyl, especially 3-methoxypropyl; and PG is anamino protecting group, or a salt thereof.
 25. An aldehyde compound ofthe formula IX according to claim 24, wherein the compound is(2R,3S,5S)-5-((1S,3S)-3-Formyl-1-hydroxy-4-methyl-pentyl)-2-[4-hydroxy-3-(3-methoxy-propoxy)-phenyl]-3-isopropyl-pyrrolidine-1-carboxylicacid tert-butyl ester, or a salt thereof. 26-65. (canceled)